[68Ga]Ga‑PSMA‑617 PET-based radiomics model to identify candidates for active surveillance amongst patients with GGG 1–2 prostate cancer at biopsy

Purpose To develop a radiomics-based model using [68Ga]Ga-PSMA PET/CT to predict postoperative adverse pathology (AP) in patients with biopsy Gleason Grade Group (GGG) 1–2 prostate cancer (PCa), assisting in the selection of patients for active surveillance (AS). Methods A total of 75 men with biopsy GGG 1–2 PCa who underwent radical prostatectomy (RP) were enrolled. The patients were randomly divided into a training group (70%) and a testing group (30%). Radiomics features of entire prostate were extracted from the [68Ga]Ga-PSMA PET scans and selected using the minimum redundancy maximum relevance algorithm and the least absolute shrinkage and selection operator regression model. Logistic regression analyses were conducted to construct the prediction models. Receiver operating characteristic (ROC) curve, decision curve analysis (DCA), and calibration curve were employed to evaluate the diagnostic value, clinical utility, and predictive accuracy of the models, respectively. Results Among the 75 patients, 30 had AP confirmed by RP. The clinical model showed an area under the curve (AUC) of 0.821 (0.695–0.947) in the training set and 0.795 (0.603–0.987) in the testing set. The radiomics model achieved AUC values of 0.830 (0.720–0.941) in the training set and 0.829 (0.624–1.000) in the testing set. The combined model, which incorporated the Radiomics score (Radscore) and free prostate-specific antigen (FPSA)/total prostate-specific antigen (TPSA), demonstrated higher diagnostic efficacy than both the clinical and radiomics models, with AUC values of 0.875 (0.780–0.970) in the training set and 0.872 (0.678–1.000) in the testing set. DCA showed that the net benefits of the combined model and radiomics model exceeded those of the clinical model. Conclusion The combined model shows potential in stratifying men with biopsy GGG 1–2 PCa based on the presence of AP at final pathology and outperforms models based solely on clinical or radiomics features. It may be expected to aid urologists in better selecting suitable patients for AS. Supplementary Information The online version contains supplementary material available at 10.1186/s40644-024-00735-2.


Introduction
Active surveillance (AS) is the recommended strategy for patients with low-risk, localized prostate cancer (PCa) and is being recommended for some intermediate-risk patients [1,2].It aims to postpone or avoid active treatment in individuals with localized PCa, while maintaining their quality of life and functional outcomes, and reducing overtreatment [1,3].However, the lack of consensus on inclusion criteria stringency and disease progression definition has led to significant variability in AS protocols across different centers and guidelines [4,5].Consequently, the cumulative five-year dropout rate on AS reaches 44%, with 27% triggered by disease progression [6,7].Given the potential for tumor progression and metastasis during AS, determining optimal selection criteria remains a crucial issue.
According to established clinical criteria and indicators, including the prostate-specific antigen (PSA), clinical T-stage, and biopsy findings, current guidelines classify patients with localized PCa into risk categories and recommend AS for all low-risk patients [8].Furthermore, AS has been proposed as an option for selected intermediate-risk PCa patients with low-volume Gleason Grade Group (GGG) 2. Several studies have demonstrated the oncologic safety of AS relative to aggressive treatment [9][10][11].However, biopsy results tend to underestimate the actual GGG of patients, resulting in some patients not meeting the enrollment criteria for receiving an AS regimen.Up to 25% of patients with biopsy GGG 1-2 PCa may qualify for AS but harbour adverse pathology (AP: pT3 and/or N1 and/or GGG ≥ 3) at radical prostatectomy (RP) [12,13].By enrolling these patients in AS, they may miss the opportunity for curative treatment due to disease progression [14,15].Additionally, the inflexibility of risk categories may limit the number of patients with pathologically indolent PCa who qualify for AS, increasing the risk of overtreatment [16].Recently, several multivariate models and nomograms based on clinical and multiparametric magnetic resonance imaging (mpMRI) features have been developed to overcome these limitations and have shown superior diagnostic efficacy compared to traditional risk categories [17,18].However, the usefulness of these models in terms of diagnostic accuracy is still controversial, and prostate biopsies for confirming PCa still tend to rely on PSA-based specificity [19].
Positron emission tomography/computed tomography (PET/CT) with [ 68 Ga]-labeled prostate-specific membrane antigen inhibitors ([ 68 Ga]Ga-PSMA) has been widely used in the clinical staging of primary PCa and the restaging of biochemically recurrent PCa [20,21].Previous studies have demonstrated a strong positive correlation between the maximal standardized uptake value (SUVmax) of [ 68 Ga]Ga-PSMA PET and GGG for primary prostate tumors, indicating its potential to predict pathological upgrade from biopsy to RP [22].The implementation of this novel molecular imaging technique could prove more advantageous than mpMRI in the patient screening process for AS [15].In recent years, the field of radiomics has rapidly progressed, offering the ability to extract valuable quantitative data from digitally encrypted medical images, thereby providing additional information on lesions [23].The combination of radiomics and machine learning has exhibited the capacity to accurately predict postoperative GGG of PCa in a non-invasive manner [24].Notably, unlike tumor biopsies, radiomics has the potential to characterize the local tumor phenotype based on the entire lesion, rather than relying on tumor subsamples.
Our study aims to develop and validate a stratified machine learning model that combines [ 68 Ga]Ga-PSMA PET/CT with traditional clinical risk factors.This model will be used to predict postoperative AP in patients with GGG 1-2 at biopsy, aiding in selecting patients for AS.

Patients
The study protocol was approved by the Ethics Committee of Xiangya Hospital Central South University, and written informed consent to use the data was obtained from all included patients.We reviewed consecutive patients with biopsy GGG 1-2 PCa from April 2020 to May 2023.All enrolled men underwent transrectal ultrasound (TRUS)-guided biopsy and were treated with RP ± lymph node dissection in the Department of Urology, Xiangya Hospital.The exclusion criteria were as follows (a) patients who had prior PCa treatment before RP; (b) patients who had missing clinical data or nonstandard examinations; (c) patients who underwent a prostate biopsy with less than 12 cores taken.Overall, 75 patients were enrolled, and clinical features such as age, total PSA (TPSA), and free PSA (FPSA) were gathered for all selected patients.
[ 68 Ga]Ga-PSMA-617 PET/CT examination and image evaluation [ 68 Ga]Ga-PSMA-617 was administered to patients intravenously, with an activity of 3.7 − 4.44 MBq/kg.PET imaging was then performed after low-dose CT scanning at 40 ± 10 min post-injection.All scans were acquired using a PET/CT scanner (690 Elite; General Electric Healthcare).First, a CT scan (140 kV; 340 mAs; pitch, 1:1; slice thickness, 3.75 mm; matrix, 512 × 512) was performed from the head to mid-thigh for anatomical localization and attenuation correction.Next, PET scanning was performed, with 1.75 min per bed position.
Finally, all PET images were reconstructed as a 256 × 256 transaxial matrix using the 3-dimensional ordered-subsets expectation maximization algorithm with 2 iterations and 23 subsets.The voxel size of the PET images was 2.7 × 2.7 × 3.8 mm.
Two experienced nuclear medicine doctors who were blind to the pathological outcomes evaluated the [ 68 Ga] Ga-PSMA-617 PET/CT images independently, with disagreements being settled through discussion.Any focal uptake above the background in the prostate that couldn't be explained by physiological uptake was considered a positive lesion.The SUVmax, the mean SUV (SUVmean), and PSMA tumor volume (PSMA-TV) were produced automatically from the volume of interest (VOI) with isocontours set at 41% of the maximum uptake within the respective focus [25,26].PSMA total lesion (PSMA-TL) was calculated by multiplying the PSMA-TV and SUVmean.

Histopathology examination
All patients participating in the study underwent TRUSguided biopsies under the supervision of an experienced urologist (Y Cai), who had performed over 1000 TRUS biopsies.RP ± pelvic lymph node dissection was subsequently performed for all patients with biopsy-proven PCa in this study using a laparoscopic approach.All of the slides from prostate biopsies and RP specimens were examined by a single, experienced uropathologist.Biopsy and pathological GGG were determined according to the 2019 International Society of Urologic Pathology (ISUP) criteria [27].Prostatectomy pathological T stage (pT) and N stage (pN) were evaluated according to American Joint Committee on Cancer (AJCC) guidelines [28].The presence of adverse pathology at RP, which is defined as non-organ confined disease (pT3) and/or lymph node invasion (pN 1) and/or GGG ≥ 3, represented the study's outcome, which means that the patient wasn't suitable for AS.For patients who were under consideration for inclusion in AS protocols, this represents a surrogate endpoint for stronger oncological outcomes.

Image segmentation
The whole prostate was manually delineated using 3D Slicer (vision 5.3.0) by two experienced nuclear medicine physicians.The entire prostate was utilized as the VOI because it avoids sampling error, radiomics problems for small lesions, and the challenges of multi-lesion characterization.It also offers a more robust inter-reader reproducibility and better accounts for tumor heterogeneity.Considering the low anatomical accuracy of PET imaging, we drew the VOI of the whole prostate on the CT images and then matched it to the PET images.To ensure accurate matching of PET and CT, manual transformation of PET images in 3 axes was allowed and the panes of PET images were interpolated to match the CT in our study.If necessary, VOI would be adjusted to prevent the inclusion of bladder activity.
After radiomics feature extraction, we used two steps to select the features.At first, the minimum redundancy maximum relevance (mRMR) algorithm, which has been proven to be effective in radiomics feature selection [30], was performed to eliminate the redundant and irrelevant features.Then, the least absolute shrinkage and selection operator (LASSO) regression model, was conducted to choose the optimized subset of features to construct the final model.

Model construction
For model development and assessment, patients were randomly divided into a training and testing group in a ratio of 7:3.All models were developed based on the training cohorts and subsequently evaluated on the testing cohorts.
The clinical model was constructed in two steps based on the clinical features.Firstly, univariate logistic regression was performed to assess clinical features including age, PSA, free PSA (FPSA), prostate volume, PSA density (PSAD), FPSA/total PSA (TPSA), biopsy GGG, % of positive cores, SUVmax, SUVmean, PSMA-TL and PSMA-TV.Then, those features with P < 0.05 in univariate logistics analysis were analyzed in multivariate logistic regression analysis to build a model.
We used a logistic regression classifier to build the radiomics model based on the selected radiomics features.A stratified tenfold cross-validation was applied with 100 iterations in the training group to develop a reliable and stable model, and the model was then assessed in the testing group.Radiomics score (Radscore) was calculated for each patient via a linear combination of selected features that were weighted by their respective coefficients.
For the combined model, clinical features with P < 0.05 in univariate logistics and Radscore were imported into the multivariate logistic regression, and statistically significant indicators were screened to establish a visualized quantitative model, the nomogram outcome stratification prediction model.

Statistical analysis
The t-tests/Spearman rank tests and Chi-square/Fisher's exact tests were used to compare the clinical features between men with AP and those without.Univariate and multivariate logistic regression analyses were performed to determine independent predictors, and then build the prediction models.
The areas under the receiver operating characteristic (ROC), area under the curve (AUC), decision curve analysis (DCA), and calibration curve were used to assess the diagnostic value, clinical utility, and predictive accuracy of those models, respectively.Statistical analysis was performed using IBM SPSS statistics software, version 26.0, and R software, version 4.1.3.P < 0.05 was considered statistically significant.

Patient characteristics
A total of 75 patients with biopsy GGG 1-2 PCa were included in this study.At final pathology after RP for all patients, 30 patients (40%) had AP.Thirty patients with AP at RP were randomly divided into the training cohort (n = 21) and the testing cohort (n = 9).Of the 45 patients without AP at RP, 32 patients were assigned to the training cohort and 13 patients were assigned to the test cohort.There were no significant differences in all clinical and image features between the training cohort and testing cohort.Table 1 shows the characteristics of all patients in detail.

Radiomics model
A total of 107 Image Biomarker Standardization Initiative (IBSI) compliant radiomic features were extracted from whole prostate PET images.Among them, 30 radiomic features were retained by mRMR.Then, the optimal adjustment weight λ (λ = 0.0672759851974577) was determined for the LASSO algorithm (Figure S1), and 6 nonzero coefficient features were selected to construct the final radiomic model.Figure S2 shows the detailed names and weights of the 6 radiomics features.
Radscore was calculated by multiplying each feature coefficient by the corresponding eigenvalue and summing.The Radscores for all patients were shown in Fig. 1.In both training and testing cohorts, the patients with AP group had a higher Radscore than patients without, and the Radscores showed great discrimination performance to distinguish between these two groups.The radiomics model yielded an AUC, sensitivity, and specificity of 0.830 (0.720-0.941), 90.5% (77.9%-100%), and 68.8% (52.7%-84.8%) in the training group.In the testing group, the radiomics model demonstrated an equal sensitivity of 77.8% (50.6%-100%) and higher specificity (overlapping 95% CIs) of 92.3% (77.8%-100%) than a clinical model, with an AUC of 0.829 (0.624-1.000) (Table 3).

Combined model
Clinical features with statistically significant differences between the two groups and Radscore were included in multivariate logistic regression to establish a combined model.The results showed that FPSA/TPSA (OR: 0.00, 95% CI: 0.00-2.21)and Radscore (OR: 9.92, 95% CI: 2.72-36.23)were the significant independent predictors of AP.A nomogram including FPSA/TPSA, and Radscore based on the combined model was shown in Fig. 2. ROC curve analysis showed that the AUC values for the combined model were 0.875 (0.780-0.970) and 0.872 (0.678-1.000) in the training and test cohorts, respectively, showing good sensitivity and specificity (Table 3).

The comparison and evaluation of the three models
A comparison of the ROC curves of these three models is shown in Figure S3.The combined model displayed the highest AUC (overlapping 95% CIs) values among the three models, with the highest sensitivity (overlapping 95% CIs) and moderate specificity in both training and testing cohorts.The Hosmer-Lemeshow calibration curves for the three predictive models were constructed in the training and testing groups.If the predicted probabilities on the calibration curve closely resembled the observed probabilities, and the P-value of the Hosmer-Lemeshow test was greater than 0.05, it indicated a high calibration accuracy of the model.In our study, it clearly demonstrated a high degree of concordance between the dotted lines (reference lines) and the coloured lines (calibration curve) in Fig. 3.In addition, the P-values of the clinical model, radiomics model, combined model were 0.303, 0.593, 0.445 in the training group, and 0.465, 0.598, 0.685 in the testing group.These results showed good agreement between the predicted and actual results.As shown in Fig. 4, DCA was performed to compare the clinical utility of the three prediction models in predicting the AP.The results indicated that the net benefit of the combined model and the radiomics model was greater than that of the clinical model.

Discussion
In this study, we developed three models based on clinical and/or [ 68 Ga]Ga-PSMA PET-based radiomics features to redefine the inclusion criteria for AS in patients with biopsy Gleason Grade Group 1-2 PCa, which may have important clinical value in maximally reducing overtreatment and avoiding inappropriate adverse pathology patients progressing.The combined model demonstrated superior predictive ability compared to the clinical and radiomics models alone, specifically in identifying patients with adverse pathology at the final analysis, who should not be considered for AS.Internal validation results revealed that the combined model effectively fulfills the clinical requirements for selecting appropriate AS candidates, leveraging the full potential of [ 68 Ga]Ga-PSMA PET/CT scans.Currently, guidelines stratify PCa patients based on biopsy results, PSA levels, and clinical stage, with AS primarily recommended for low-risk patients [8].However, the strict inclusion criteria of AS limit the inclusion of suitable patients.Moreover, the limited number of included indicators omits some patient information, leading to the inclusion of patients who may not be appropriate for AS, resulting in delays in their treatment [16,31].To extend the AS inclusion criteria and reduce the inclusion of unsuitable patients, several predictive models based on clinical characteristics and conventional imaging features have been developed in recent years.Gandaglia et al. [32] developed a multivariable model using patients' PSA levels, clinical stage, biopsy grade group, number of positive cores, and PSA density to assess the risk of poor outcomes in low-risk or intermediate-risk PCa patients, aiding in the selection of AS candidates.The results demonstrated a 10% increase in the number of patients eligible for AS compared to PRIAS criteria, without increasing the risk of misclassification [33].However, the diagnostic efficacy of this model remains poor, possibly due to the absence of specific imaging characteristics from prostate MRI and [ 68 Ga]Ga-PSMA PET/CT.Another study, which developed a multivariable model including variables from MRI and targeted biopsy, validated that the inclusion of MRI features significantly enhanced the diagnostic performance of the model for adverse pathology [16].This improvement may be attributed to the correlation between PI-RADS scores and adverse pathology, as well as the more accurate pathology obtained through MRI-targeted biopsy.Previous studies have shown that [ 68 Ga]Ga-PSMA PET/CT is a more accurate predictor of adverse pathological outcomes compared to mpMRI [15,34].In addition, previous literatures have proved that PSMA PET-targeted biopsy, combined with the technique of intraoperative quantification of PSMA PET uptake in core biopsies, could improve the detection rate of csPCa compared with systematic biopsy and reduce the need for saturation biopsy [35].In our study, we developed a clinical model based on patients' clinical characteristics and conventional PSMA PET/CT features (FPSA/TPSA and PSMA-TV), which demonstrated improved diagnostic performance.However, it is undeniable that the lesion  features provided by visual assessment of PSMA PET/ CT are limited, and the acquisition of some features is subjective.
Radiomics can extract features in a high-throughput and quantitative manner that cannot be obtained through visual evaluation by clinicians.This can improve the accuracy of diagnosis, prognosis, and prediction [36,37].Currently, research on utilizing radiomics data to select patients for AS is limited and predominantly based on MRI imaging [38][39][40].Compared to models using clinical and imaging visual evaluation features, radiomics models based on MRI imaging often exhibit similar or slightly lower diagnostic performance [38,39].This discrepancy may stem from the inherent challenge of MRI images in differentiating various PCa pathologies.Considering the potential of PET-derived radiomics as biomarkers for predicting treatment outcomes and characterizing tumor biology in a non-invasive manner is noteworthy [41].Specifically, radiomic features derived from [ 68 Ga]Ga-PSMA-11 PET/CT images have shown remarkable proficiency in discerning Gleason scores [24].Our study presents the pioneering application of [ 68 Ga]Ga-PSMA PET radiomics in selecting patients for AS.Encouragingly, our results demonstrate that the radiomics model based on PSMA PET imaging outperforms clinical models in terms of diagnostic performance in both the training and testing sets, confirming the ability of [ 68 Ga]Ga-PSMA PET to identify adverse postoperative pathology in patients with AS.Advances in technology have revolutionized the management of PCa, with mounting evidence supporting the adoption of sophisticated tests and comprehensive features to individualize patient assessment and ensure optimal treatment [42].The proposed radiomics-based analysis incorporating the clinical-radiographic feature could provide a noninvasive biomarker for the individualized and precise medical treatment of patients [40].In our study, we developed a predictive model incorporating PSMA PET imaging, histology features, and FPSA/TPSA, which exhibited superior diagnostic performance compared to both clinical and imaging histology models, with consistent results in the test set.This underscores the complementary nature of clinical and imaging histology features and the increased robustness achieved through their combination.Current major clinical guidelines, including the European Association of Urology (EAU) guideline, recommend active surveillance as the treatment of choice for patients with low-risk prostate cancer.In our internal validation queue, the use of our combined model to select AS candidates would allow for an 83.3% increase in the number of patients eligible for AS without increasing the risk of adverse pathological characteristics compared to the EAU criteria.
Our combined model also showed excellent calibration characteristics at internal validation.Notably, among patients with a predicted risk of AP greater than 40%, the model would underestimate the actual risk of AP.Some individuals with AP might receive an AS regimen.Among patients with a predicted risk of AP less than 40%, the model would overestimate the actual risk of AP.Some individuals without AP might excluded from an AS regimen.Furthermore, we employed nomogram plots to enhance the visualization and clinical utility of the model, providing a clear representation of the impact of each factor on the target event for individual patients.In clinical practice, these nomogram plots can facilitate the scoring of patients based on their clinical and imaging histology features, enabling the assessment of their probability of harboring adverse pathology.As a result, they provide guidance to clinicians in selecting appropriate AS patients.Radiomics features are arguably more dependent on the underlying image data.A recent meta-analysis suggests that [ 68 Ga]Ga-PSMA and [ 18 F]F-DCFPyL PET have comparable diagnostic performance in patients with suspected prostate cancer [43].A study including 160 men found that the SUVmax of [ 18 F]F-PSMA and [ 68 Ga]Ga-PSMA did not differ (P > 0.05) in local Fig. 2 Nomogram based on the combined model predicting AP at RP, among patients with biopsy GGG 1-2 PCa.AP adverse pathology, RP radical prostatectomy, GGG Gleason Grade Group, PCa prostate cancer, Radscore radiomics score, FPSA free prostate-specific antigen, TPSA total prostate-specific antigen recurrence or primary prostate cancer [44].These results seem to indicate that there is no difference in the uptake of [ 18 F]-and [ 68 Ga]-labeled PSMA ligands in prostate cancer PET scans.However, the [ 68 Ga]-labeled PSMA ligand used in these studies is [ 68 Ga]Ga PSMA-11, and there is limited data on [ 68 Ga]Ga-PSMA-617.In addition, there are no studies that have investigated whether the value of PET-based radiomics features is valid for different PSMA ligands.Further multicentre, large-scale studies will be required to establish with certainty the accuracy and wider applicability of the radiomic signature proposed here.
Several limitations are evident in this study.Firstly, the sample size was relatively small due to strict inclusion criteria.And external validation is lacking in the present study, which may restrict the generalizability of our results.Future validation would benefit from additional multicenter, large-scale studies.Secondly, the study's endpoint of AP at RP is a surrogate outcome for cancer-specific survival in AS patients.However, this limitation is common in most studies as intermediate-risk patients are usually offered active treatment.Finally, this study did not incorporate MRI-related visual assessments and imaging histology features because the MRI examinations for most patients were conducted at external hospitals, which could result in substantial differences between MRI image acquisition and interpretation.

Fig. 1
Fig. 1 Bar diagrams of Radscore for each patient in the training cohort (a) and testing cohort (b).The red bars are Radscore values for patients with adverse pathology at final pathology, and the green bars are Radscore values for patients with favorable disease at final pathology.Radscore, radiomics score

Fig. 3
Fig. 3 The calibration curves of the three models in the training cohort (a) and testing cohort (b).The P-values of the clinical model, radiomics model, combined model were 0.303, 0.593, 0.445 in the training group, and 0.465, 0.598, 0.685 in the testing group

Fig. 4
Fig. 4 DCA of the clinical, radiomics, and combined models for predicting AP at final pathology in the testing cohort.DCA decision curve analysis, AP adverse pathology

Table 2
Univariate and multivariate Logistic analysis of clinical factors for predicting patients with adverse pathologyOR odds ratio, CI confidence interval, PSA prostate-specific antigen, FPSA free prostate-specific antigen, PV prostate volume, PSAD prostate-specific antigen density, TPSA total prostate-specific antigen, GGG Gleason Grade Group, SUVmax maximum standardized uptake values, SUVmean mean standardized uptake values, PSMA-TL prostate-specific membrane antigen total lesion, PSMA-TV prostate-specific membrane antigen tumour volume

Table 3
Diagnostic performance of three models in training and testing cohorts AUC area under curve, PPV positive predictive value, NPV negative predictive value